Anti-thyroglobulin T cell receptors
Disclosed is a synthetic T cell receptor (TCR) having antigenic specificity for an HLA-A2-restricted epitope of thyroglobulin (TG), TG 470-478 . Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells are also provided. Antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.
1. A method of treating cancer in a mammal in need thereof, comprising administering to the mammal
(a) one or more host cells expressing at least one of (i)-(vi):
(i) a T cell receptor (TCR) having antigenic specificity for the amino acid sequence of SEQ ID NO: 2 and comprising an α chain complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 3, an α chain CDR2 comprising the amino acid sequence of SEQ ID NO: 4, an α chain CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a β chain CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a β chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a β chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8,
(ii) a polypeptide comprising a functional portion of the TCR of (i), wherein the functional portion comprises the amino acid sequences of SEQ ID NOs: 3-8,
(iii) a polypeptide comprising a functional portion of the TCR of (i), wherein the functional portion comprises the amino acid sequence of both SEQ ID NOs: 9 and 10,
(iv) a polypeptide comprising a functional portion of the TCR of (i), wherein the functional portion comprises the amino acid sequence of both SEQ ID NOs: 11 and 12,
(v) a protein comprising at least one of the polypeptides of any one of (ii)-(iv), and
(vi) a protein comprising a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 3-5 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 6-8, or
(b) a pharmaceutical composition comprising the one or more cells of (a) and a pharmaceutically acceptable carrier
in an amount effective to treat the cancer in the mammal, wherein the cancer expresses a human thyroglobulin (hTG) peptide comprising an amino acid sequence of SEQ ID NO: 2.
2. The method of claim 1 , wherein the cancer is thyroid cancer or neuroblastoma.
3. The method of claim 1 , wherein the TCR comprises an α chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a β chain variable region comprising the amino acid sequence of SEQ ID NO: 10.
4. The method of claim 1 , wherein the TCR further comprises an α chain constant region comprising the amino acid sequence of SEQ ID NO: 13 and a β chain constant region comprising the amino acid sequence of SEQ ID NO: 14.
5. The method of claim 1 , wherein the TCR comprises an α chain comprising the amino acid sequence of SEQ ID NO: 11 and a β chain comprising the amino acid sequence of SEQ ID NO: 12.
6. The method of claim 1 , wherein the polypeptide comprises a TCR α chain, a TCR β chain, and a self-cleaving, viral linker peptide, wherein the linker peptide is positioned between the TCR α and β chains.
7. The method of claim 1 , wherein the protein of (vi) comprises a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 9 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 10.
8. The method of claim 1 , wherein the protein of (vi) comprises a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 11 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 12.
9. The method of claim 1 , wherein the protein of (vi) is a fusion protein.
10. The method of claim 1 , wherein the protein of (vi) is a recombinant antibody.
11. The method of claim 1 , wherein the one or more host cells is/are human.
12. The method of claim 1 , wherein the method comprises administering to the mammal a host cell expressing the TCR of (i).
13. The method of claim 1 , wherein the method comprises administering to the mammal a population of cells comprising at least one host cell expressing the TCR of (i).